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Multiple system atrophy (MSA) is a devastating neurodegenerative disorder that presents with a variety of symptoms that can be categorized broadly into two phenotypic groups, either parkinsonism or cerebellar ataxia. These phenotypes reflect the predominant neuronal cell loss that occurs in several brain regions including caudate, putamen, substantia nigra, cerebellum, pons, inferior olives, and spinal cord. The pathogenic hallmark of MSA is the presence of glial cytoplasmic inclusions (GCIs) in oligodendroglia of affected brain regions. GCIs are protein aggregates that contain an abundance of α-synuclein, which implicates this neuronal protein in a central role for MSA pathogenesis despite its normal absence from oligodendroglia.

Since the first description of GCIs, MSA researchers have wondered whether the disease process begins in neurons or oligodendroglia. This important question is perhaps best addressed by developing MSA animal models that mimic the pathological and behavioral aspects of the disease. Animal models of MSA have proven difficult to generate because they often fail to replicate the entire scope of glial pathology and neuronal cell loss. By developing a transgenic mouse that overexpresses human α-synuclein in oligodendroglia via the oligodendroglia-specific CNP promoter, Yazawa and colleagues (Yazawa et al., 2005) have effectively recapitulated many aspects of MSA. Not only do M2 mice exhibit GCI formation in oligodendroglia, they also display a slow progression of behavioral deficits that are preceded by neuronal deficits (e.g., axonal atrophy) in cerebrum and spinal cord. Loss of neurons and oligodendroglia was revealed only in spinal cord. The sequence of these events suggests that oligodendroglial abnormalities are the primary cause of MSA.

This work further establishes a critical role for α-synuclein in MSA pathology and neurodegeneration. It supports the prediction that an overabundance of α-synuclein in oligodendroglia is a key event in MSA pathogenesis. However, α-synuclein is not normally expressed in oligodendroglia of mouse brain (Yazawa et al., 2005) or human brain (Solano et al., 2000). Clearly, a future advance in MSA research will be determining the cause for ectopic overabundance of α-synuclein in GCI-containing oligodendroglia.

Curiously, the M2 mice lack neuronal cell loss in many brain regions commonly affected in MSA, such as substantia nigra. This indicates that α-synuclein overexpression alone is not adequate for truly replicating the complexities of MSA pathology. Future studies will likely examine whether substantia nigra and other brain regions are more vulnerable to toxic insults in M2 mice than in non-transgenic mice. Perhaps neuronal vulnerability to mitochondrial inhibitors such as 3-nitroproprionic acid will be enhanced in M2 mice, as was recently demonstrated in similar mice that overexpress α-synuclein in oligodendroglia via the proteolipid protein (PLP) promoter (Stefanova et al., 2005). Such evidence supports the idea of a “multi-hit” scheme for MSA pathogenesis in which mitochondrial dysfunction may play a role.

Along with PLP-α-synuclein mice (Kahle et al., 2002), the M2 mice provide the means to examine the potential downstream effects of α-synuclein overabundance in oligodendroglia. Such analysis will likely reveal toxic mechanisms of neuronal cell death in MSA, thereby providing novel targets for MSA therapeutics. Hopefully, other diseases in which glial deficits lead to neuronal cell loss will also benefit from such advances.